The present application claims priority to co-pending U.S. patent application Ser. No. 60/332,806, filed Nov. 14, 2001, and is a continuation-in-part of U.S. Ser. No. 09/415,890, filed Oct. 8, 1999, which was a continuation of U.S. Ser. No. 08/911,607, filed Aug. 15, 1997, now U.S. Pat. No. 6,045,815. The entire text of the above-referenced provisional application disclosure is specifically incorporated by reference herein without disclaimer.
1. Field of the Invention
The present invention relates generally to the fields of infectious conditions and drug formulations. More particularly, it concerns the development of a pharmaceutical formulation of Pimaricin (also called as Natamycin) that can be used to treat and prevent a wide variety of topical infections caused by fungal and microbial pathogens.
2. Description of Related Art
Superficial fungal infections constitute one of the more difficult challenges for clinicians caring for patients with diabetes mellitus and/or immunocompromised states, such as those caused by cancer, cancer-therapy and HIV-infection (Anaissie et al., 1989). While the incidence of hematogenous candidiasis in immunocompromised patients has decreased significantly with the introduction of fluconazole, the occurrence of superficial opportunistic infections affecting the mucous membranes and the skin of immunocompromised patients and have persisted and pose a major clinical problem carrying also the risk of serving as an entry port for systemic infection. The most common of such infections is oral thrush and vaginal candida infections.
The use of either physician-prescribed or over the counter dispensed topical antifungal therapy for vaginal fungal infections appears to have increased gradually over the last decade. The indiscriminant use of azole compounds in this setting and its concomitant use as prophylaxis against systemic candida infection after cancer chemotherapy and in AIDS-patients has raised the incidence of resistance against such azole-based antifungal therapy.
The polyene antibiotic Amphotericin B (AMB), which typically is the first-line treatment for documented or suspected systemic mold infections, is associated with side effects such as substantial local toxicity and irritation. Furthermore, inflammation of the mucosal surface with which it comes in contact is seen in >75% of treated subjects. In addition, AMB is largely ineffective against Fusariosis.
Thus, an effective antimycotic agent with low local organ toxicity, broad antifungal spectrum activity, predictable lack of systemic absorption after topical administration and activity against both Fusarium spp. and Aspergillus spp. appears highly warranted.
Pimaricin, also called as Natamycin, is an effective anti-fungal agent, exerting significant activity against molds and yeast, particularly of the Candida, Trichomonas, Aspergillus and Fusarium species. Pimaricin is especially effective in molds and yeasts that are resistant to azole compounds and to Amphotericin B.
Pimaricin was first isolated in 1955 from a strain of Streptomyces (Struyk et al., 1957-1958). Pimaricin exhibited a wide range of in vitro activity against fungi, yeast, and trichomonads (Struyk et al., 1957-1958; Korteweg et al., 1963; Raab, 1972). The drug was found to have little or no toxicity after oral administration, being virtually non-absorbable from the gastrointestinal tract (Korteweg et al., 1963; Raab, 1972). In fact, pimaricin's prominent chemical stability, paired with its apparent lack of intestinal absorption and systemic toxicity, formed the basis for its FDA-approved use in the food industry, where it is used to prevent the proliferation of aflatoxin-producing molds (Code of Federal Regulations, Food and Drugs, 1995).
The lack of solubility of pimaricin in various solvents, both aqueous and organic, that are compatible for human administration severely restricted its use in clinical medicine. Past attempts to solubilize pimaricin in vehicles that are safe for intravascular administration in humans have all failed, despite the hard work by Stuyk and others (Struyk et al., 1957-1958; U.S. Pat. No. 3,892,850; Korteweg et al., 1963; Raab, 1972). Korteweg and coworkers attempted to solubilize the drug by mixing it with a complex polysaccharide (Korteweg et al., 1963). Although the water-solubility of this formulation increased dramatically, its antifungal in vitro activity decreased to about ⅓ of that of native Natamycin. Further, this preparation is comparatively toxic in experimental animals, and it was therefore deemed unsuitable for systemic parenteral administration in humans (Struyk et al., 1957-1958).
Other attempts to prepare pimaricin based creams for topical treatments of genital infections has resulted in formulations in which the pimaricin is present in a predominantly insoluble crystalline form (Christensen and Buch, 1982; WO 93/07884). Thus, attempts to solubilize Natamycin and make formulations that were applicable for topical application were unsuccessful and led to clinical trials that demonstrated that natamcyin was inferior to alternative drugs for relief of infections such as vaginal fungal infections (Sawyer et al., 1975; Christensen and Buch, 1982). This is not unexpected, since Natamycin is virtually insoluble in most solvent vehicles hence, topical formulations of Natamycin consist of mainly crystallized Natamycin suspended in a cream base. The art has also not addressed the concentrations of solubilized Natamycin that is available in these formulations versus the concentration of Natamycin suspended in crystallized form in the ointment base.
Although, there are reports of success with the crystalline suspensions of pimaricin in corneal fungal infections (Lavingia and Dave, 1986) and the prevention of such infections in contact-lens users, the amount of soluble and biologically active pimaricin in these formulations is very small. These opthalmologic studies have however demonstrated the superiority of pimaricin as compared with AMB in regards to local tissue tolerance to polyene antibiotic treatment. Thus, the insolubility of pimaricin is an obstacle that needs to be overcome.
As described in U.S. Pat. No. 6,045,815, the present inventors have had success in solubilizing pimaricin for parenteral formulations. Parenteral formulations of pimaricin are useful in treating systemic infections such as disseminated fungal infections that are often seen in patients with hematological cancers. Such parenterally acceptable, nontoxic formulations of pimaricin are beneficial not only for cancer patients, but also for other groups of immunocompromised patients, e.g. those suffering from HIV and those having recently undergone open heart surgery, all of which are commonly targets for opportunistic systemic infections.
However, to date there is no topical formulation of pimaricin that has solubilized pimaricin that is in a form that is available to combat infections. Given that a variety of pathogens that are normally susceptible to pimaricin cause topical infections such as but not limited to vaginal infections, ano-genital infections, skin infections, athletes foot, and the like, the development of an effective topical pharmaceutical formulation with activity against a variety of infectious agents is highly desirable.